Compositions for the treatment of cataracts

ABSTRACT

In one embodiment, the present application discloses an aqueous ophthalmic composition for the treatment of eye diseases, lesions and injuries, comprising: a) one steroid, or a combination of at least two steroids selected from the group consisting of lanosterol, dihydrolanosterol, 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, 4,4-dimethylcholesta-8,24-dien-3β-ol, 4,4-dimethylcholesta-8-en-3β-ol, 4,4-dimethylcholesta-8(9),14-dien-3β-ol, 14-desmethyl lanosterol, lathosterol, Δ7.24-cholestadienol, cholesterol, cholesta-7-enol, cholesteryl ester, 7-dehydrocholesterol, desmosterol, 7-dehydrodesmosterol, zymosterol, 27-hydroxycholesterol, cholesta-7,24-dien-3-β-ol, cholesta-8(9)-en-3-β-ol, 5α-cholestan-3β-6-one, 5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO3H (5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO3H,25-ol (5-cholesten-3β-sulfate,25-ol), 5-cholesten-3β,25-diol, disulfate, and their esters thereof, or a pharmaceutically acceptable salt thereof, in a concentration effective for the treatment and/or prophylaxis of the eye diseases, lesions and injuries; and b) a pharmaceutical excipient; and methods of treatment using such compositions.

PRIORITY APPLICATIONS

This application incorporates the embodiments disclosed in U.S.Provisional Application No. 62/295,267, filed Feb. 15, 2016, U.S.Provisional Application No. 62/252,120, filed Nov. 6, 2015, U.S.Provisional Application No. 62/202,518 filed Aug. 7, 2015 and U.S.Provisional Application No. 62/197,477, filed Jul. 27, 2015, which areall incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cataracts are the leading cause of blindness. Millions of patients everyyear undergo cataract surgery to remove the opacified lenses. Surgicaltreatment of cataracts, while effective, is not without risk ofcomplications. It has been reported that congenital cataract is one ofthe common causes of visual impairment and childhood blindness.Congenital cataract occurs in an isolated fashion or as one component ofa multi-system disorder. Nonsyndromic congenital cataracts have anestimated incidence of 1-6 per 10,000 live births. Nearly one-third ofthe cases show a positive family history, of which autosomal dominantinheritance is the most common. More than 20 genes have been identifiedresponsible for isolated autosomal dominant congenital cataract. Thesegenes encode crystallins, membrane transport proteins, cytoskeletalprotein, and transcription factors. Crystallin proteins, including α-,β- and γ-crystallins, represent about 90% of lens soluble proteins inhuman. These proteins play critical roles in the optical transparencyand high refractive index. α-Crystallins belong to the family of thesmall heat-shock proteins, acting as a molecular chaperone that protectsproteins from misfolding. β- and γ-Crystallins, considered as asuperfamily, are lens structural proteins and share a common two-domainstructure, composed of four Greek-key motifs. γ-Crystallins include sixmembers encoded by a gene cluster (CRYGA-F) on human chromosome 2. SeeXiao-Qiao Li et al., Human Mutation, Research Article, Vol. 33, Issue 2,pp. 391-401, February 2012.

Zhao et al. (2015) The human lens is comprised largely of crystallinproteins assembled into a highly ordered, interactive macro-structureessential for lens transparency and refractive index. Any disruption ofintra- or inter-protein interactions will alter this delicate structure,exposing hydrophobic surfaces, with consequent protein aggregation andcataract formation. Cataracts are the most common cause of blindnessworldwide, affecting tens of millions of people, and currently the onlytreatment is surgical removal of cataractous lenses. The precisemechanisms by which lens proteins both prevent aggregation and maintainlens transparency are largely unknown. Lanosterol is an amphipathicmolecule enriched in the lens. It is synthesized by lanosterol synthase(LSS) in a key cyclization reaction of a cholesterol synthesis pathway.Two distinct homozygous LSS missense mutations (W581R and G588S) in twofamilies with extensive congenital cataracts. Both of these mutationsaffect highly conserved amino acid residues and impair key catalyticfunctions of LSS. Engineered expression of wild-type, but not mutant,LSS prevents intracellular protein aggregation of variouscataract-causing mutant crystallins. Treatment by lanosterol, but notcholesterol, significantly decreased preformed protein aggregates bothin vitro and in cell-transfection experiments. Zhao et al. have alsodemonstrated that lanosterol treatment could reduce cataract severityand increase transparency in dissected rabbit cataractous lenses invitro and cataract severity in vivo in dogs. Zhao et al. identifiedlanosterol as an important compound in the prevention of lens proteinaggregation and suggested a novel strategy for cataract prevention andtreatment. See Ling Zhao et al., Lanosterol reverses protein aggregationin cataract, Nature, Research Letters, July, 2015. Similarly, Makley etal., Science, Vol. 350, Issue 6261, pp. 674-677, reported theadministration of certain sterols as pharmacological chaperones forα-crystallin for partially restoring transparency in cataract models.

The foregoing examples of the related art and limitations are intendedto be illustrative and not exclusive. Other limitations of the relatedart will become apparent to those of skill in the art upon a reading ofthe specification and a study of the drawings or figures as providedherein.

SUMMARY OF THE INVENTION

There is a need for effective non-invasive and non-surgical methods forthe treatment of cataracts, including congenital cataracts. The presentapplication dicloses novel formulations and methods for the preventionand treatment of cataracts. The following embodiments, aspects andvariations thereof are exemplary and illustrative are not intended to belimiting in scope.

In one embodiment, the present application discloses compositionscomprising a combination of steroids, such as lanosterol, and steroidsthat are formed downstream in the lanosterol or cholesterol biosyntheticpathway that are effective for the treatment of eye diseases, such aseye diseases, lesions and injuries, including cataracts. In anotherembodiment, the steroids include their prodrugs, such as their esters,including methyl esters and ethyl esters. In one embodiment, the mixtureof steroids include lanosterol. In one variation of each of theembodiments, variations and aspects disclosed herein, the steroidformulation exclude lanosterol; and the steroid formulation excludecholesterol as a single steroid.

In another embodiment, the present application discloses compositionscomprising lanosterol that is effective for the treatment of eyediseases, such as lesions and injuries, including cataracts. In anotherembodiment, the lanosterol include the prodrugs, such as their esters,including methyl esters and ethyl esters.

In one embodiment, the present application discloses a method for thetreatment of cataracts using the disclosed compositions or formulations.In one aspect, the present application discloses formulations andcompositions, and methods for the treatment of cataracts, including themutation of γC-crystallin in a patient with autosomal dominantcongenital cataract.

In one embodiment, there is provided an aqueous ophthalmic compositionfor the treatment of eye diseases, lesions and injuries, comprising:

a) one steroid or a combination of at least two steroids selected fromthe group consisting of lanosterol, dihydrolanosterol,4,4-dimethylcholesta-8(9),14,24-trien-3β-ol,4,4-dimethylcholesta-8,24-dien-3β-ol, 4,4-dimethylcholesta-8-en-3β-ol,4,4-dimethylcholesta-8(9),14-dien-3β-ol, 14-desmethyl lanosterol,lathosterol, Δ^(7.24)-cholestadienol, cholesterol, cholesta-7-enol,cholesteryl ester, 7-dehydrocholesterol, desmosterol,24-dehydrocholesterol), 7-dehydrodesmosterol, zymosterol,27-hydroxycholesterol, cholesta-7,24-dien-3-β-ol,cholesta-8(9)-en-3-β-ol, 5α-cholestan-3β-ol-6-one,5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol), 5-cholesten-3β,25-diol, disulfate, andtheir esters thereof, or a pharmaceutically acceptable salt thereof, ina concentration effective for the treatment and/or prophylaxis of theeye diseases, lesions and injuries; and b) a pharmaceutical excipient.

In one variation of the above, the steroid is selected from the groupconsisting of 5α-cholestan-3β-ol-6-one, 5-cholesten-3β,25-diol,5-cholesten-3β,25-OSO₃H (5-cholesten-3β,25-sulfate),5-cholesten-3β-OSO₃H,25-ol (5-cholesten-3β-sulfate,25-ol) and5-cholesten-3β,25-diol. In another variation, the combination or mixtureof steroids is selected from the group consisting of5α-cholestan-3β-ol-6-one, 5-cholesten-3β,25-diol,5-cholesten-3β,25-OSO₃H (5-cholesten-3β-sulfate),5-cholesten-3β-OSO₃H,25-ol (5-cholesten-3β-sulfate,25-ol) and5-cholesten-3β,25diol. In another variation, the mixture of two steroidsis selected from 5α-cholestan-3β-ol 6-one and one steroid, or at leastone steroid selected from the group consisting of5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol) and 5-cholesten-3β,25-diol.

In one variation, there is provided a pharmaceutical compositionsuitable for topical administration to an eye, comprising: (a) onesteroid or at least two steroids selected from the group consisting oflanosterol, dihydrolanosterol,4,4-dimethylcholesta-8(9),14,24-trien-3β-ol,4,4-dimedthylcholesta-8,24-dien-3β-ol, 4,4-dimethylcholesta-8-en-3β-ol,4,4-dimethylcholesta-8(9),14-dien-3β-ol, 14-desmethyl lanosterol,lathosterol, Δ^(7.24)-cholestadienol, cholesterol, cholesta-7-enol,cholesteryl ester, 7-dehydrocholesterol, desmosterol,(24-dehydrocholesterol), 7-dehydrodesmosterol, zymosterol,27-hydroxycholesterol, cholesta-7,24-dien-3-β-ol,cholesta-8(9)-en-3-β-ol, 5α-cholestan-3β-ol-6-one,5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol), 5-cholesten-3β,25-diol, disulfate, or apharmaceutically acceptable salt thereof in a concentration effectivefor treatment and/or prophylaxis of the eye diseases, lesions andinjuries; (b) a pharmaceutically acceptable cyclodextrin compound in acyclodextrin concentration sufficient to maintain the steroids insolution; and (c) at least one or at least two ophthalmically compatiblepolymers selected from the group consisting of konjac and sodiumalginate; konjac and hydroxy propyl guar; konjac and propylene glycolalginate; konjac and Carbopol 971; hydroxy propyl guar and agarose;propylene glycol alginate and agarose; and propylene glycol alginate andscleroglucan. In one variation of the above, the steroid is selectedfrom the group consisting of 5α-cholestan-3β-ol-6-one,5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol ) and 5-cholesten-3β,25-diol. In anothervariation, the combination or mixture of steroids, or the at least twosteroids is selected from the group consisting of5α-cholestan-3β-ol6one, 5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol) and 5-cholesten-3β,25-diol. In anothervariation, the mixture of two steroids is selected from5α-cholestan-3β-ol-6-one and one steroid selected from the groupconsisting of 5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol) and 5-cholesten-3β,25-diol.

In one variation of the above composition or formulation, lanosterol ispresent as a component of the composition. In another variation,lanosterol is present as the only steroid in the composition orformulation. In another variation of the composition, lanosterol ispresent at a concentration of at least 50%, at least 60%, at least 70%,at least 80%, at least 90% and at least 95% of the steroids mixture. Inanother variation of the composition, the concentration of the steroidin the composition is about 1 to 100 mM, 1 to 75 mM, 1 to 50 mM, 1 to 25mM, or 1 to 10 mM. In another variation, the concentration of thesteroid in the composition is about 50 to 100 mM, 75 to 100 mM, 85 to100 mM, or 90 to 100 mM. In another variation, the concentration of thesteroid in the composition is about 25 to 75 mM, 35 to 65 mM, or about45 to 55 mM.

In one variation of the above, the composition or formulation is atopical pharmaceutical formulation. In one aspect, the presentformulations overcome one of the major problems encountered with topicaldelivery of ophthalmic drugs that is the rapid and extensive precornealloss due to drainage and high tear fluid turnover.

In another aspect of the composition, the eye disease is cataract. Inanother aspect, the composition further comprises at least one celluloseselected from a group consisting of carboxymethylcellulose,hydroxyethylcellulose and hydroxypropylmethylcellulose, apharmacologically acceptable salt thereof, or a mixture thereof. Inanother variation, the formulation further comprisescarboxypolymethylene or polyvinylpyrrolidone.

In one variation, the composition is suitable for topical administrationto the eye. In another variation, the amount of the carboxypolymethyleneor polyvinylpyrrolidone is effective to increase the intraocularabsorption of the steroid, for example, in the eye and/or in the aqueoushumor.

In yet another variation, the formulation comprises a cyclodextrincompound in a concentration sufficient to ensure that essentially all ofthe steroid agent in the composition is in solution. In one aspect, thecyclodextrin compound is selected from the group consisting ofα-cyclodextrin, β-cyclodextrin, λ-cyclodextrin, an alkylcyclodextrin, ahydroxyalkylcyclodextrin, a carboxyalkyl-cyclodextrin, andsulfoalkylether cyclodextrin. In another variation, the cyclodextrincompound is selected from the group consisting ofhydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin. In onevariation of the above, the cyclodextrin concentration is about 1 mg/mlto about 500 mg/ml, 10 mg/ml to about 400 mg/ml, 100 mg/ml to about 300mg/ml or 150 mg/ml to about 250 mg/ml. In another variation, thecyclodextrin concentration is about 1 mg/ml to about 250 mg/ml, 1 mg/mlto about 200 mg/ml, 1 mg/ml to about 150 mg/ml or 1 mg/ml to about 100mg/ml.

In another aspect of the above composition, the total concentration ofthe steroids in the composition is about 0.001 to 1.0 mg/ml. In anotheraspect, the composition provides a dose range of the steroids at about0.01 to about 100 mg/kg/day.

In one variation of the above composition, the dose range is 0.1 toabout 100 mg/kg/day. In another variation, the dose range is 0.1 to 50mg/kg/day, 0.1 to 25 mg/kg/day, 0.1 to 20 mg/kg/day, 0.1 to 15mg/kg/day, or 0.1 to 10 mg/kg/day. In another variation, the dose rangeis 50 to 100 mg/kg/day, 60 to 100 mg/kg/day, 75 to 100 mg/kg/day, 85 to100 mg/kg/day, 90 to 100 mg/kg/day, or 95 to 100 mg/kg/day. In anothervariation, the dose range is 25 to 75 mg/kg/day, 30 to 75 mg/kg/day, 45to 75 mg/kg/day, 50 to 75 mg/kg/day, 60 to 75 mg/kg/day, or 65 to 75mg/kg/day.

In another aspect of the composition, the amount of the steroid in thecomposition is in the range of 0.0005% to 0.5% wt/wt, 0.001% to 0.5%wt/wt, 0.01% to 0.5% wt/wt or 0.1% to 0.5% wt/wt. In another aspect ofthe composition, the amount of the cellulose is about 0.01% to 0.5%. Inone variation of the composition, the amount of the cellulose is about0.2% to 0.4%, 0.25% to 0.35% or about 0.3%. In one variation of theabove, the composition is a steroid formulation (100 mg)-loadednanoparticles. In another variation, the steroid formulation in thenanoparticles is 0.01 to 100 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to10 mg or 0.01 to 1 mg.

In another aspect of the above, the composition further comprises apreservative selected from benzyl alcohol or para-amino-benzoic acid. Inanother aspect, the composition of the steroids or the ratio of thesteroids are as disclosed in Tables 1 to 8, as disclosed herein. Inanother aspect, the above composition further comprises a lubricantwhich is acceptable for topical administration to the eye. In anotheraspect, the composition is suitable for daily administration to the eye.In yet another aspect of the above composition, the composition issuitable for administration daily for at least 1 week.

In one variation, the composition comprises a therapeutically effectiveamount of the steroid, and a pharmaceutically acceptable excipient. Inone aspect the above, the composition is suitable for dailyadministration to the eye.

In one variation, the composition may be administered daily, every 2days, every 3 days, every 4 days, every 5 days, or weekly for at leastone week; or the composition may be administered at least 2 weeks, atleast 3 weeks or at least 4 weeks or more. In another variation, thecomposition may be administered accordingly, at least once a day or atleast twice a day for the above noted period of time. In anothervariation, the composition is suitable for administration topicallytwice daily for 4 weeks or more. In another variation, the compositionis suitable for administration topically for 6 months or more.

In another variation, the composition is suitable for use as amedicament to treat eye diseases, lesions and injuries, and wherein thecomposition is suitable for administration in combination with other eyemedications.

In another aspect of the above, the composition may be administereddaily, every 2 days, every 3 days, every 4 days, every 5 days, or weeklyfor at least one week.

In another embodiment, there is provided a method for the treatment ofeye diseases, lesions and injuries, the method comprising anadministration of a composition comprising: a) one steroid or acombination of at least two steroids selected from the group consistingof lanosterol, dihydrolanosterol,4,4-dimethylcholesta-8(9),14,24-trien-3β-ol,4,4-dimethylcholesta-8,24-dien-3β-ol, 4,4-dimethylcholesta-8-en-3β-ol,4,4-dimethylcholesta-8(9),14-dien-3β-ol, 14-desmethyl lanosterol,lathosterol, Δ^(7.24)-cholestadienol, cholesterol, cholesta-7-enol,cholesteryl ester, 7-dehydrocholesterol, desmosterol,(24-dehydrodesmosterol, 7-dehydrocholesterol, zymosterol,27-hydroxycholesterol, cholesta-7,24-dien-3-β-ol,cholesta-8(9)-en-3-β-ol, 5α-cholestan-3β-ol-6-one,5-cholesten-3β,25-diol, 5-cholesten-3β,25-OSO₃H(5-cholesten-3β,25-sulfate), 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol), 5-cholesten-3β,25-diol, disulfate, andtheir esters thereof, or a pharmaceutically acceptable salt thereof, ina concentration effective for the treatment and/or prophylaxis of theeye diseases, lesions and injuries; and b) a pharmaceutical excipient;to a patient in need thereof.

In one aspect of the above method, the eye disease is cataracts. Inanother aspect of the method, the administration is effective to preventthe formation of cataracts or effective to treat cataracts. In anotheraspect of the above method, the administration of the compositionreverses protein aggregation in cataracts or significantly reduces theseverity of the cataract and increases the lens clarity.

In another aspect of the above method, the administration of thecomposition significantly inhibits aggresome formation of both wild-typeand mutated crystalline proteins.

In one variation of the above, the methods reverse cataracts in thepatient. In one variation of the above, the methods are effective in atleast one of suppressing, partially suppressing or partially reversingamyloid formation. In another aspect, the disclosed methods blockaggregation and reverse or partially reverse R120G cryAB(αβ-crystallin), cryAB and cryAA insolubility in the protein content ofa lens. In another aspect, the methods bind and stabilize crystallins.In another aspect, the methods stabilize the soluble forms of cryAB andsuppress its aggregation. In another aspect, the disclosed methods iseffective in a number of ways, including restoring protein solubility;improving the solubility of the α-crystallins, including cryAA andcryAB; improving transparency as determined by at least one grade on theLOCS III scoring system; reversing protein aggregation by binding andstabilizing the more soluble forms of cryAA and cryAB; and stabilizingthe native forms of cryAB. The above methods are effective by at least20%, at least 30%, at least 40%, at least 50%, at least 70%, at least80% at least 90% or at least 95%. In one variation, the method reducesthe severity of the cataract by at least 50%, at least 70%, at least 80%at least 90% or at least 95%. In another variation, the administrationof the composition to the eye results in the release of mutantcrystalline proteins from aggregation. In another variation, theadministration of the composition re-dissolves the aggregated crystallinproteins from the amyloid-like fibrils in the lens tissues of the eye.In another variation, the administration is effective to reduceintraocular pressure on chronic topical ocular and of primary open-angleglaucoma and ocular hypertension.

In another aspect of the above methods, the composition may beadministered to patients with primary open-angle glaucoma-, ocularhypertension with accompanying cataracts.

In another embodiment, there is provided a method for inhibiting lensprotein aggregation, treating cataract, reducing cataract formation,reducing cataract severity and increased lens clarity comprising theadministration of a composition of any of the above compositions and asdisclosed herein.

In another embodiment, there is provided a method for decreasing proteinaggregation caused by mutant crystallin proteins culture and reducingpreformed cataract severity by increasing lens clarity, the methodcomprising the administration of a composition of any one of any one ofthe above, and as disclosed herein. In one aspect of the above method,the therapeutically effective amount is effective to treat cataract. Inanother aspect of the above methods, the administration is a topicaladministration.

In one variation, the therapeutically effective amount is effective toinhibiting lens protein aggregation, treating cataract, reducingcataract formation, reducing cataract severity and increased lensclarity. In another variation of the above method, the method compriseadministering a pharmaceutically effective amount of the steroids to apatient in need of treatment, wherein a pharmaceutically effectiveamount of the steroid comprises an amount sufficient to ameliorate thedisease.

In one embodiment, the pharmacologically acceptable salts of celluloseinclude carboxymethylcellulose sodium and sodium cellulose glycolate.The USP describes carboxymethylcellulose sodium as the sodium salt of apolycarboxymethyl ether of cellulose. A typical molecular weight for thecellulose is 90,000-700,000. Cellulose compounds suitable for use in thepresent formulation are commercially available in various forms fromvarious manufacturers. Benzene-free carboxypolymethylene is commerciallyavailable under the trademark CARBOMER 980. Polyvinylpyrrolidone iscommercially available under the trademark KOLLIDON K17. In onevariation of each of the embodiments, variations and aspects disclosedherein , the steroid formulations exclude lanosterol.

In another embodiment, the formulation comprises at least one, or atleast two ophthalmically compatible compounds and polymers selected fromthe group consisting of konjac and sodium alginate; konjac and hydroxypropyl guar; konjac and propylene glycol alginate; konjac and Carbopol971; hydroxy propyl guar and agarose; propylene glycol alginate andagarose; and propylene glycol alginate and scleroglucan.

Also included in the above embodiments, aspects and variations are saltsof amino acids such as arginate and the like, gluconate, andgalacturonate. Some of the compounds of the invention may form innersalts or Zwitterions. Certain of the compounds of the present inventioncan exist in unsolvated forms as well as solvated forms, includinghydrated forms, and are intended to be within the scope of the presentinvention. Certain of the above compounds may also exist in one or moresolid or crystalline phases or polymorphs, the variable biologicalactivities of such polymorphs or mixtures of such polymorphs are alsoincluded in the scope of this invention. Also provided arepharmaceutical compositions comprising pharmaceutically acceptableexcipients and a therapeutically effective amount of at least onecompound of this invention.

Pharmaceutical compositions of the compounds of this invention, orderivatives thereof, may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, 5% dextrose in water or buffered sodium orammonium acetate solution. Such formulations are especially suitable forparenteral administration but may also be used for oral administration.Excipients, such as polyvinylpyrrolidinone, gelatin, hydroxycellulose,acacia, polyethylene glycol, mannitol, sodium chloride, or sodiumcitrate, may also be added. Alternatively, these compounds may beencapsulated, tableted, or prepared in an emulsion or syrup for oraladministration. Pharmaceutically acceptable solid or liquid carriers maybe added to enhance or stabilize the composition, or to facilitatepreparation of the composition. Liquid carriers include syrup, peanutoil, olive oil, glycerin, saline, alcohols or water. Solid carriersinclude starch, lactose, calcium sulfate, dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar, orgelatin. The carrier may also include a sustained release material suchas glyceryl monostearate or glyceryl distearate, alone or with a wax.The amount of solid carrier varies but, preferably, will be betweenabout 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulation, and compressing, when necessary,for tablet forms; or milling, mixing, and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion, or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule. Suitable formulations for each ofthese methods of administration may be found in, for example, Remington:The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition,Lippincott, Williams & Wilkins, Philadelphia, Pa.

In one variation, there is provided the above steroids, or apharmaceutically acceptable salts thereof, and as applicable withrespect to their possible isomers, in the form of a single stereoisomeror mixture of stereoisomers thereof.

In addition to the exemplary embodiments, aspects and variationsdescribed above, further embodiments, aspects and variations will becomeapparent by reference to the tables and figures and by examination ofthe following descriptions.

DETAILED DESCRIPTION OF THE INVENTION Definitions:

Unless specifically noted otherwise herein, the definitions of the termsused are standard definitions used in the art of organic synthesis andpharmaceutical sciences. Exemplary embodiments, aspects and variationsare illustratived in the figures and drawings, and it is intended thatthe embodiments, aspects and variations, and the figures and drawingsdisclosed herein are to be considered illustrative and not limiting.

Mammals that may be treated according to the methods of the presentapplication include humans, canines (dogs), cats, rabbits and equines.

By “eye diseases” it is meant eye disorders including cataract,open-angle primary glaucoma, corneal disorders, presbyopia, computervision syndrome, eye strain, ocular inflammation, blurred vision, dryeye syndrome, retinal diseases, vitreous opacities and lesions,complications of diabetes mellitus and other systemic diseases. In oneembodiment, the eye disease is cataract.

The term “gum”, refers to any synthetic or non-synthetic polymer,natural polysaccharide, or derivatized natural polysaccharide that isophthalmically compatible and that increases the viscosity of a solutionor formulation sufficiently to increase the viscosity of the solution orformulation in which it is found or to transform a drop of the solutioninto a semi-solid or gelatinous state after administration to an eye ofa patient. Non-exclusive examples of synthetic polymer gums includepolyethylene glycol, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol and derivatives thereof, and Carbopol and derivativesthereof. Non-exclusive examples of natural polysaccharide gums includecarrageenan, konjac, sodium alginate, aloe vera gel, agarose, guar,pectin, tragacanth, acacia, Arabic, curdlan, gellan, xanthan,scleroglucan, hyaluronic acid, or chitosan. Non-exclusive examples ofderivatized natural polysaccharide gums include propyleneglycol alginateand hydroxypropyl guar.

The clause “ophthalmic composition” or “ophthalmic formulation” refersto a composition for application to the eye or its related orsurrounding tissues such as, for example, the eyelid. The term alsoincludes compositions for treating conditions of the eye itself or thetissues surrounding the eye. The ophthalmic composition can be appliedtopically or by other techniques, known to persons skilled in the art,such as injection to the eye or its related tissues. Examples ofsuitable topical administration to the eye include administration in eyedrops and by spray formulations. A further suitable topicaladministration route is by subconjunctival injection. The formulationsmay also be provided to the eye periocularly or retro-orbitally. Incertain embodiments, intracameral administration may be employed.

The clause “flowable mucoadhesive polymer” refers to acarboxy-containing polymer, for example, lightly crosslinked polymers ofacrylic acid or the like, having an optimal in vivo mucosal absorptionrate, safety, degradability and flowability for an eye drop. Theflowable mucoadhesive polymers used in the present application are waterinsoluble, water-swellable, biodegradable polymer carriers includinglightly crosslinked carboxy-containing polymers such as polycarbophil(Noveon™ AA-1, Lubizol Corp., Wickliffe, Ohio) or other Carbopol™polymers (Lubizol Corp., Wickliffe, Ohio). Suitable carboxy-containingpolymers for use in the present invention and methods for making themare described in U.S. Pat. No. 5,192,535. A suitable carboxy-containingpolymer system for use in the present application include DuraSite™(InSite Vision Inc., Alameda, Calif.), containing polycarbophil, whichis a sustained release topical ophthalmic delivery system that releasesdrug at a controlled rate. The polymer systems include lightlycrosslinked polymers that are prepared by suspension or emulsionpolymerizing at least about 90% by weight of a carboxyl-containingmono-ethylenically unsaturated monomer such as acrylic acid with fromabout 0.1% to about 5% by weight of a polyfunctional, or difunctional,crosslinking agent such as divinyl glycol (3,4-dihydroxy-1,5-hexadiene),having a particle size of not more than about 50 μm in equivalentspherical diameter, when formulated with an ophthalmic medicament, suchas the steroid formulation, into solutions or suspensions in aqueousmedium in which the amount of polymer ranges from about 0.5% to about1.5% by weight, based on the total weight of the aqueous suspension. Inone embodiment, the pH is from about 7.4 to about 8.5, and the osmoticpressure (osmolality or tonicity) is from about 10 mOsM to about 400mOsM, provide a topical ophthalmic medicament delivery systems havingsuitably low viscosities for administration to the eye in drop form.These formulations may rapidly gel in the eye after coming into contactwith the eye's tear fluid to a substantially greater viscosity than thatof the originally-introduced suspension or solution and thus remain inplace for prolonged periods of time to provide sustained release of theophthalmic medicament.

“Pharmaceutically acceptable salts” means salt compositions that isgenerally considered to have the desired pharmacological activity, isconsidered to be safe, non-toxic and is acceptable for veterinary andhuman pharmaceutical applications. Such salts include acid additionsalts formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, and the like; or with organicacids such as acetic acid, propionic acid, hexanoic acid, malonic acid,succinic acid, malic acid, citric acid, gluconic acid, salicylic acidand the like.

The clause “sustained release delivery system” or “sustained releasecomposition” refers to a formulation or composition comprising aflowable mucoadhesive polymer, which may be a carboxy-containing polymersuch as polycarbophil and DuraSite™, as described in U.S. Pat. No.5,192,535, that facilitates a sustained release of the steroidformulation. The sustained release delivery systems, formulations orcompositions may be prepared in many forms or shapes, such as asolution, a gel, a film, a pellet, a rod, a filament, a cylinder, adisc, a wafer, nanoparticles or a microparticle. A “microparticle” asdefined herein, comprises a blend polymer component having a diameter ofless than about one millimeter and having the steroid formulationdispersed therein. A microparticle can have a spherical, non-sphericalor irregular shape. In one aspect, the microparticle will be of a sizesuitable for injection. In another aspect, the size range formicroparticles is from about one to about 50 microns in diameter.

The clause “steroid formulation” or “steroids formulation” as usedherein may include a single steroid that is lanosterol, or may includeat least two steroids comprising lanosterol and a second steroiddisclosed herein. In another embodiment, the term “steroid formulation”may include a single steroid that is not lanosterol, or at least twosteroids disclosed in the specification, such as the compounds orsteroids in Tables 1 to 9.

“Therapeutically effective amount” means an amount of the steroids thatelicit any of the biological effects listed in the specification.

The term “treating” or “treatment” refers to reducing, amelioratingreversing, alleviating, inhibiting the progress of, or preventing adisease or a medical condition of the eye itself or the tissuesurrounding the eye or the symptoms associated therewith. The term alsoencompasses prophylaxis, therapy and cure. The subject or patientreceiving “treatment,” or whom undergoes “treating” is any mammal inneed of such treatment for (eye-related diseases, such as cataracts,inflammation or inflammatory conditions, or combinations thereof),including primates, in such as humans, and other mammals such asequines, cattle, swine and sheep; and domesticated mammals and pets ingeneral.

The following Tables provide illustrative representations of differentformulations with a variation in the ratio of the steroids that may beused in the formulation. In one aspect, the total amount of the steroidsin the composition may be in the range of 0.0005% to 0.5% wt/wt, 0.0005%to 0.2% wt/wt, 0.0005% to 0.1% wt/wt or as disclosed herein.

TABLE 1 Formulation Numbers Ratio of Steroids by % wt/wt Steroids 1 2 34 5 6 7 8 9 10 11 12 13 14 15 Lanosterol 95 95 95 95 95 95 95 95 95 9595 95 95 95 95 Dihydrolanosterol 2 2 1 1 1 — — — — — — — — — —4,4-Dimethylcholesta- 2 1 1 1 1 1 2 2 2 2 1 1 1 1 —8(9),14,24-trien-3β-ol 4,4-Dimethylcholesta- 1 1 1 — — 1 1 1 — — 1 1 1 1— 8,24-dien-3β-ol 4,4-Dimethylcholesta- — — — — — — — — 1 — — — 1 1 28(9),14-dien-3β-ol 4,4-Dimethylcholesta- — — — — — — — — 1 2 — — 1 — 18-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — — lanosterolLathosterol — — — — 1 — — — — — — — — — 1 Δ^(7,24)-Cholestadienol — 1 11 — 1 1 — 1 1 1 2 1 — 1 Cholesterol — — — — — — — — — — — — — — —Cholesta-7-enol — — — — — — — — — — — — — — — Cholesteryl ester — — — —— — — — — — — — — — — 7-Dehydrocholesterol — — — — — — — — — — — — — — —Desmosterol (24- — — — 1 1 1 1 1 — — 1 1 — 1 — dehydrocholesterol)7-Dehydrodesmosterol — — — — — — — — — — — — — — — Zymosterol — — 1 1 11 — 1 — — 1 — — 1 — 27- — — — — — — — — — — — — — — — HydroxycholesterolCholesta-7,24-dien-3- — — — — — — — — — — — — — — — β-olCholesta-8(9)-en-3-β- — — — — — — — — — — — — — — — ol — Means noneadded to formulation.

TABLE 2 Formulation Numbers Ratio of Steroids by % wt/wt Steroids 16 1718 19 20 21 22 23 24 25 26 27 28 29 30 Lanosterol 90 90 90 90 90 90 9090 90 90 90 90 90 90 90 Dihydrolanosterol 4,4- 5 3 2 2 1 5 5 5 5 5 7 7 77 — Dimethylcholesta- 8(9),14,24-trien- 3β-ol 4,4- — 1 1 — — 2 1 1 — — 11 — 1 — Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 3 — — — 11 7 Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 1 2 — — 1— 1 Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — —— — lanosterol Lathosterol — — — — 1 — — — — — — — — — 1Δ^(7,24)-Cholestadienol — 1 1 1 1 3 — 1 1 1 2 — — 1 Cholesterol — — — —1 — — — — — — — — — — Cholesta-7-enol — — — — — — — — — — — — — — —Cholesteryl ester — — — — — — — — — — — — — — — 7-Dehydro- — — — — — — —— — — — — — — — cholesterol Desmosterol (24- — — — 1 1 1 1 2 — 1 1 — 1 1— dehydrocholesterol) 7- — — — — — — — — — — — — — — —Dehydrodesmosterol Zymosterol — — 1 1 1 1 — 2 — 1 — — — — — 27- — — — —— — — — — — — — — — — Hydroxycholesterol Cholesta-7,24-dien- — — — — — —— — — — — — — — — 3-β-ol Cholesta-8(9)-en-3- — — — — — — — — — — — — — —— β-ol — Means none added to formulation.

TABLE 3 Formulation Numbers Ratio of Steroids by % wt/wt Steroids 31 3233 34 35 36 37 38 39 40 41 42 43 44 45 Lanosterol 80 80 80 80 80 80 8080 80 80 80 80 80 80 80 Dihydrolanosterol 10 10 10 10 10 — — — — — — — —— — 4,4- 10 3 5 5 5 10 10 10 10 10 15 15 15 15 — Dimethylcholesta-8(9),14,24-trien- 3β-ol 4,4- — 3 1 — — 5 1 1 — — 1 1 — 3 —Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 3 — — — 2 1 15Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 4 5 — — 1 — 1Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — —lanosterol Lathosterol — — — — 1 — — — — — — — — — 1 Δ^(7,24)- — 1 2 2 11 5 — 3 2 1 2 — — 1 Cholestadienol Cholesterol — — — — 1 — — — — — — — —— — Cholesta-7-enol — — — — — — — — — — — — — — — Cholesteryl ester — —— — — — — — — — — — — — — 7-Dehydro- — — — — — — — — — — — — — — —cholesterol Desmosterol (24- — 1 — 1 1 2 4 5 — 2 1 — 2 1 —dehydrocholesterol) 7- — — — — — — — — — — — — — — — DehydrodesmosterolZymosterol — 2 2 2 1 2 — 4 — 1 2 2 — — 2 27- — — — — — — — — — — — — — —— Hydroxycholesterol Cholesta-7,24- — — — — — — — — — — — — — — —dien-3-β-ol Cholesta-8(9)-en- — — — — — — — — — — — — — — — 3-β-ol —Means none added to formulation.

TABLE 4 Formulation Numbers Ratio of Steroids by % wt/wt Steroids 46 4748 49 50 51 52 53 54 55 56 57 58 59 60 Lanosterol 70 70 70 70 70 70 7070 70 70 70 70 70 70 70 Dihydrolanosterol 10 10 10 10 10 — — — — — — — —— — 4,4- 10 5 5 5 5 20 20 20 20 20 15 15 15 15 — Dimethylcholesta-8(9),14,24-trien- 3β-ol 4,4- 10 5 5 — — 3 1 1 — — 10 1 — 5 —Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 5 — — — 10 3 15Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 2 5 — — 1 — 1Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — —lanosterol Lathosterol — — — — 5 — — — — — — — — — 1Δ^(7,24)-Cholestadienol — 5 5 5 5 3 5 — 3 2 1 4 — — 1 Cholesterol — — —— 3 — — — — — — — — — — Cholesta-7-enol — — — — — — — — — — — — — — —Cholesteryl ester — — — — — — — — — — — — — — — 7-Dehydrocholesterol — —— — — — — — — — — — — — — Desmosterol (24- — 5 — 5 1 2 4 4 — 2 1 — 2 2 —dehydrocholesterol) 7- — — — — — — — — — — — — — — — DehydrodesmosterolZymosterol — — 5 5 1 2 — 5 — 1 3 10 2 5 2 27- — — — — — — — — — — — — —— — Hydroxycholesterol Cholesta-7,24- — — — — — — — — — — — — — — —dien-3-β-ol Cholesta-8(9)-en- — — — — — — — — — — — — — — — 3-β-ol —Means none added to formulation.

TABLE 5 Formulation Numbers Ratio of Steroids by % wt/wt Steroids 61 6263 64 65 66 67 68 69 70 71 72 73 74 75 Lanosterol 60 60 60 60 60 60 6060 50 50 50 50 50 50 50 Dihydrolanosterol 20 20 20 20 20 — — — — — — — —— — 4,4- 10 5 5 5 5 20 20 20 30 30 30 15 15 15 — Dimethylcholesta-8(9),14,24-trien- 3β-ol 4,4- 10 5 5 — — 3 1 1 — — 10 1 — 5 —Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 10 — — — 20 3 25Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 5 5 — — 1 — 1Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — —lanosterol Lathosterol — — — — 5 — — — — — — — — — 1Δ^(7,24)-Cholestadienol — 5 5 5 5 3 5 — 5 5 1 4 — — 1 Cholesterol — — —— 3 — — — — — — — — — — Cholesta-7-enol — — — — — — — — — — — — — — —Cholesteryl ester — — — — — — — — — — — — — — — 7-Dehydrocholesterol — —— — — — — — — — — — — — — Desmosterol (24- — 5 — 5 1 7 4 4 — 5 1 10 2 22 dehydrocholesterol) 7- — — — — — — — — — — — — — — —Dehydrodesmosterol Zymosterol — — 5 5 1 7 10 15 — 5 8 20 2 15 20 27- — —— — — — — — — — — — — 10 — Hydroxycholesterol Cholesta-7,24- — — — — — —— — — — — — — — — dien-3-β-ol Cholesta-8(9)-en- — — — — — — — — — — — —10 — — 3-β-ol — Means none added to formulation.

TABLE 6 Formulations Numbers Relative Ratios of Steroids in FormulationsSteroids 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 Lanosterol 10 1010 10 10 10 10 10 5 5 5 5 5 5 5 Dihydrolanosterol 5 1 1 1 1 — — — — — —— — — — 4,4- 5 1 1 1 1 1 2 2 2 2 1 1 1 1 — Dimethylcholesta-8(9),14,24-trien- 3β-ol 4,4- 1 1 1 — — 1 1 1 — — 1 1 1 1 —Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 1 — — — 1 1 2Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 1 2 — — 1 — 1Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — —lanosterol Lathosterol — — — — 1 — — — — — — — — — 1 Δ^(7,24)- — 1 1 1 —1 1 — 1 1 1 2 1 — 1 Cholestadienol Cholesterol — — — — — — — — — — — — —— — Cholesta-7-enol — — — — — — — — — — — — — — — Cholesteryl ester — —— — — — — — — — — — — — — 7-Dehydrocholesterol — — — — — — — — — — — — —— — Desmosterol (24- — — — 1 1 1 1 1 — — 1 1 — 1 — dehydrocholesterol)7- — — — — — — — — — — — — — — — Dehydrodesmosterol Zymosterol — — 1 1 11 — 1 — — 1 — — 1 — 27- — — — — — — — — — — — — — — — HydroxycholesterolCholesta-7,24- — — — — — — — — — — — — — — — dien-3-β-olCholesta-8(9)-en- — — — — — — — — — — — — — — — 3-β-ol — Means noneadded to formulation.

TABLE 7 Formulations Relative Ratios of Steroids in FormulationsSteroids 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 Lanosterol 55 5 5 5 5 5 5 3 3 3 3 3 3 1 Dihydrolanosterol 1 1 1 1 1 — — — — — — — —— — 4,4- 1 1 1 1 1 1 2 2 2 2 1 1 1 1 — Dimethylcholesta-8(9),14,24-trien- 3β-ol 4,4- 1 1 1 — — 1 1 1 — — 1 1 1 1 —Dimethylcholesta- 8,24-dien-3β-ol 4,4- — — — — — — — — 1 — — — 1 1 —Dimethylcholesta- 8(9),14-dien-3β-ol 4,4- — — — — — — — — 1 2 — — 1 — —Dimethylcholesta- 8-en-3β-ol 14-Desmethyl — — — — — — — — — — — — — — —lanosterol Lathosterol — — — — 1 — — — — — — — — — —Δ^(7,24)-Cholestadienol — 1 1 1 — 1 1 — 1 1 1 2 1 — — Cholesterol — — —— — — — — — — — — — — — Cholesta-7-enol — — — — — — — — — — — — — — —Cholesteryl ester — — — — — — — — — — — — — — — 7- — — — — — — — — — — —— — — — Dehydrocholesterol Desmosterol (24- — — — 1 1 1 1 1 — — 1 1 — 1— dehydrocholesterol) 7- — — — — — — — — — — — — — — — Dehydro-desmosterol Zymosterol — — 1 1 1 1 — 1 — — 1 — — 1 — 27- — — — — — — — —— — — — — — — Hydroxycholesterol Cholesta-7,24-dien- — — — — — — — — — —— — — — — 3-β-ol Cholesta-8(9)-en-3- — — — — — — — — — — — — — — —5α-cholestan- 1 1 3 5 — — — — — — — — 3 5 5 3β-ol-6- one5α-cholestan-3β-ol- — — — — — 5 5 5 5 1 5 5 3 5 5 6-one5-cholesten-3β,25- — — — — 5 5 — — — — — — — — — diol 5-cholesten-3β,25-— — — — — — — — — — — — — 1 — OSO₃H (5-cholesten- 3β,25-sulfate)5-cholesten-3β,25- — 1 3 5 — — — 5 3 1 3 — — — 5 diol, disulfate5-cholesten-3β- — — — — — — — — — — 1 5 — — — OSO₃H,25-ol (5-cholesten-3β- sulfate,25-ol) — Means none added to formulation.

TABLE 8 Formulations Relative Ratios of Steroids in FormulationsSteroids 106 107 108 109 110 111 112 113 114 115 Lanosterol — — 1 1 — —— 1 1 — Dihydrolanosterol — — — — — — — — — — Zymosterol — — — — — — — —— — 5α-cholestan- 1 1 1 1 1 — — — — — 3β-ol-6-one 5α-cholestan- — — — —— — — — — 1 3β-ol-6-one 5-cholesten- — — — — — — — — — — 3β,25-diol5-cholesten-3β,25- — — — — — — — — — — OSO₃H (5-cholesten-3β,25-sulfate) 5-cholesten-3β, 1 — 1 1 1 1 — 1 1 — 25-diol, disulfate5-cholesten-3β- — — — — 1 — 1 1 — 1 OSO₃H,25-ol (5-cholesten-3β-sulfate,25-ol) — Means none added to formulation.

TABLE 9 Formulation Numbers Quantity of Steroids Steroids 116 117 118119 120 121 Lanosterol 50 mg 30 mg 50 mg — Sodium — 30 mg 50 mg 50 mg —100 mg cholesteryl sulfate 5-cholesten- 50 mg 30 mg 50 mg 55 mg3β,25-diol

The use of the above representative formulations show that the disclosedmethods are effective, or are improved, by at least 20%, at least 30%,at least 40%, at least 50%, at least 70%, at least 80% at least 90% orat least 95% over the results obtained in the absence of using thedisclosed methods. In one aspect, the method reduces the severity of thecataract by at least 50%, at least 70%, at least 80% at least 90% or atleast 95%.

Experimentals:

25-Hydroxycholesterol (5-cholesten-3β,25-diol, 5-cholestene-3β,25-diol),98%, H1015 Sigma, CAS Number 2140-46-7; C₂₇H₄₆O₂, MW 402.65, BeilsteinRegistry Number 3161259. Sodium cholesteryl sulfate (5-cholesten-3β-olsulfate sodium salt, cholesterol 3-sulfate sodium salt, cholesterylsodium sulfate, cholesteryl sulfate sodium salt) C9523 Sigma, CAS Number2864-50-8, C₂₇H₄₅NaO₄S, MW 488.70, Beilstein Registry Number 3899884.Lanosterol (3β-hydroxy-8,24-lanostadiene, 8,24-lanostadien-3βol) (≥93%,powder), L5768 Sigma, CAS Number 79-63-0, C₃₀H₅₀O, MW 426.72. DMSO(dimethyl sulfoxide, D1435), CAS Number 67-68-5. Acetonitrile,glycerine, carboxymethylcellulose, benzyl alcohol, phenyl-ethyl alcohol,potassium borate, potassium bicarbonate, Carbomer 980, polyhexamethylenebiguanide (PHMB), phosphate buffer, Poloxamer 237, Polysorbate 80,castor oil, edetate disodium, sodium chloride, potassium chloride,polycaprolactone (PCL) polymer, lecithin,1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethyleneglycol) 2000 are commercially available, such as from Sigma-Aldrich.

Illustrative Formulations:

The formulations listed below are set forth for illustrative purposesonly, and are not to be used to limit the proper construction of theclaims. The formulations may comprise the steroids having differentratio in the compositions or formulations, such as those illustrated inTables 1 to 9.

1. Aqueous Ophthalmic Composition for Treatment of Eye Disease: Anillustrative formulation for treatment of eye disease, such as cataract,is set forth below:

Steroid Formulation No. 1:

Deionized water, 970 grams; glycerine (1.0%) 13 grams; a steroidformulation of Tables 1 to 8; carboxymethylcellulose (0.3%) 3 grams;benzyl alcohol (0.3%) 3 grams; potassium borate, 7.9 grams; potassiumbicarbonate 3.4 grams or as needed to adjust the pH to 6.3-6.5.

2. Aqueous Ophthalmic Composition for Treatment of Eye Disease

Illustrative Steroid Formulation No. 2 employs benzyl alcohol and sodiumbuffers:

Steroid Formulation No. 2:

Deionized water 970 grams; glycerine (1.0%) 13 grams; a steroidformulation of Tables 1 to 8; carboxymethylcellulose (0.3%) 3 grams;phenyl-ethyl alcohol (0.3%) 3 grams; sodium borate 7.9 grams and sodiumbicarbonate 3.4 grams or as needed to adjust the pH to 6.3-6.5.

3. Aqueous Ophthalmic Composition for Treatment of Eye Disease

Illustrative Steroid Formulation No. 3 employs Carbomer 980:

Steroid Formulation No. 3:

Deionized water, 970 grams; glycerine (1.0%) 13 grams; a steroidformulation of Tables 1 to 8; carbomer 980, 2 grams; benzyl alcohol(0.3%) 3 grams; potassium borate, 7.9 grams; potassium bicarbonate, 3.4grams or as needed to adjust the pH to 6.3-6.5.

4. Aqueous Ophthalmic Composition for Treatment of Cataracts

An illustrative formulation for treatment of an eye disease,particularly cataract, is set forth below:

Steroid Formulation No. 4:

Deionized water, 970 grams; glycerine (1.0%) 13 grams; a steroidformulation of Tables 1 to 8; carboxymethylcellulose (0.3%) 3 grams;benzyl alcohol (0.3%) 3 grams; potassium borate 7.9 grams and potassiumbicarbonate 3.4 grams or as needed to adjust the pH to 6.3-6.5.

Steroid Formulation No. 5:

Deionized water 970 grams; glycerine, 13 grams; a steroid formulation ofTables 1 to 8 (0.001 to 0.05 wt/vol %); p-aminobenzoic acid, 0.07 grams;carboxymethylcellulose, 3 grams; benzyl alcohol, 3 grams; potassiumborate, 7.9 grams; potassium bicarbonate, 3.4 grams or as needed toadjust the pH to 6.3-6.5.

Steroid Formulation No. 116:

116.A. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of lanosterol, 50 mg of 5-cholesten-3β,25-diol, 2.0 ml of absoluteethanol, 10 drops of DMSO and 8.0 ml of a stock sterile aqueous solutioncomprising 0.0001% polyhexamethylene biguanide (PHMB), phosphate buffer(0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %), edetate disodium (0.05wt/vol %), sodium chloride (0.9 wt/vol %) and potassium chloride (0.05wt/vol %) in double distilled water. The resulting solution was stirredat room temperature for 15 minutes where a small amount of insolublebeige particulates remain present as a suspension in the solution. Thesolution was transferred to a 10 ml sealable plastic (PET, LDPE) liquiddropper bottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous, slightly turbidsolution.

116.B. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of lanosterol, 50 mg of 5-cholesten-3β,25-diol, 2.0 ml of absoluteethanol, 10 drops of DMSO and 8.0 ml of a stock sterile aqueous solutioncomprising 0.0001% polyhexamethylene biguanide (PHMB), phosphate buffer(0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %), polysorbate 80 (0.1wt/vol %), castor oil (0.1 wt/vol %), edetate disodium (0.05 wt/vol %),sodium chloride (0.9 wt/vol %) and potassium chloride (0.05 wt/vol %) indouble distilled water. The resulting solution was stirred at roomtemperature for 15 minutes where a small amount of insoluble beigeparticulates remain present as a suspension in the solution. Thesolution was transferred to a 10 ml sealable plastic (PET, LDPE) liquiddropper bottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous solution.

Steroid Formulation No. 117:

117.A. Into a 30 ml glass beaker with a magnetic stir bar was added 30mg of lanosterol, 30 mg of 5-cholesten-3β,25-diol, 30 mg sodiumcholesteryl sulfate, 2.0 ml of absolute ethanol, 10 drops of DMSO and8.0 ml of a stock sterile aqueous solution comprising 0.0001%polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol %),Poloxamer 237 (0.05 wt/vol %), edetate disodium (0.05 wt/vol %), sodiumchloride (0.9 wt/vol %) and potassium chloride (0.05 wt/vol %) in doubledistilled water. The resulting solution was stirred at room temperaturefor 15 minutes where a small amount of insoluble off-white particulatesremain present as a suspension in the solution. The solution wastransferred to a 10 ml sealable plastic (PET, LDPE) liquid dropperbottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous, slightly turbidsolution.

117.B. Into a 30 ml glass beaker with a magnetic stir bar was added 30mg of lanosterol, 30 mg of 5-cholesten-3β,25-diol, 30 mg sodiumcholesteryl sulfate, 2.0 ml of absolute ethanol, 10 drops of DMSO and8.0 ml of a stock sterile aqueous solution comprising 0.0001%polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol %),Poloxamer 237 (0.05 wt/vol %), polysorbate 80 (0.1 wt/vol %), castor oil(0.1 wt/vol %), edetate disodium (0.05 wt/vol %), sodium chloride (0.9wt/vol %) and potassium chloride (0.05 wt/vol %) in double distilledwater. The resulting solution was stirred at room temperature for 15minutes where a small amount of insoluble off-white particulates remainpresent as a suspension in the solution. The solution was transferred toa 10 ml sealable plastic (PET, LDPE) liquid dropper bottle and capped toseal the solution. The resulting bottle was sonicated in a water bath atroom temperature for 40 minutes to disperse and dissolve the suspension,resulting in a homogeneous solution.

Steroid Formulation No. 118:

118.A. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of lanosterol, 50 mg of sodium cholesteryl sulfate, 2.0 ml ofabsolute ethanol, 10 drops of DMSO and 8.0 ml of a stock sterile aqueoussolution comprising 0.0001% polyhexamethylene biguanide (PHMB),phosphate buffer (0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %), edetatedisodium (0.05 wt/vol %), sodium chloride (0.9 wt/vol %) and potassiumchloride (0.05 wt/vol %) in double distilled water. The resultingsolution was stirred at room temperature for 15 minutes where a smallamount of insoluble beige particulates remain present as a suspension inthe solution. The solution was transferred to a 10 ml sealable plastic(PET, LDPE) liquid dropper bottle and capped to seal the solution. Theresulting bottle was sonicated in a water bath at room temperature for40 minutes to disperse and dissolve the suspension, resulting in ahomogeneous, slightly turbid solution.

118.B. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of lanosterol, 50 mg of sodium cholesteryl sulfate, 2.0 ml ofabsolute ethanol, 10 drops of DMSO and 8.0 ml of a stock sterile aqueoussolution comprising 0.0001% polyhexamethylene biguanide (PHMB),phosphate buffer (0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %),polysorbate 80 (0.1 wt/vol %), castor oil (0.1 wt/vol %), edetatedisodium (0.05 wt/vol %), sodium chloride (0.9 wt/vol %) and potassiumchloride (0.05 wt/vol %) in double distilled water. The resultingsolution was stirred at room temperature for 15 minutes where a smallamount of insoluble beige particulates remain present as a suspension inthe solution. The solution was transferred to a 10 ml sealable plastic(PET, LDPE) liquid dropper bottle and capped to seal the solution. Theresulting bottle was sonicated in a water bath at room temperature for40 minutes to disperse and dissolve the suspension, resulting in ahomogeneous solution.

Steroid Formulation No. 119:

119.A. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of 5-cholesten-3β,25-diol, 50 mg of sodium cholesteryl sulfate, 2.0ml of absolute ethanol, 10 drops of DMSO and 8.0 ml of a stock sterileaqueous solution comprising 0.0001% polyhexamethylene biguanide (PHMB),phosphate buffer (0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %), edetatedisodium (0.05 wt/vol %), sodium chloride (0.9 wt/vol %) and potassiumchloride (0.05 wt/vol %) in double distilled water. The resultingsolution was stirred at room temperature for 15 minutes where a smallamount of insoluble beige particulates remain present as a suspension inthe solution. The solution was transferred to a 10 ml sealable plastic(PET, LDPE) liquid dropper bottle and capped to seal the solution. Theresulting bottle was sonicated in a water bath at room temperature for40 minutes to disperse and dissolve the suspension, resulting in ahomogeneous, slightly turbid solution.

119.B. Into a 30 ml glass beaker with a magnetic stir bar was added 50mg of 5-cholesten-3β,25-diol, 50 mg of sodium cholesteryl sulfate, 2.0ml of absolute ethanol, 10 drops of DMSO and 8.0 ml of a stock sterileaqueous solution comprising 0.0001% polyhexamethylene biguanide (PHMB),phosphate buffer (0.2 wt/vol %), Poloxamer 237 (0.05 wt/vol %),polysorbate 80 (0.1 wt/vol %), castor oil (0.1 wt/vol %), edetatedisodium (0.05 wt/vol %), sodium chloride (0.9 wt/vol %) and potassiumchloride (0.05 wt/vol %) in double distilled water. The resultingsolution was stirred at room temperature for 15 minutes where a smallamount of insoluble beige particulates remain present as a suspension inthe solution. The solution was transferred to a 10 ml sealable plastic(PET, LDPE) liquid dropper bottle and capped to seal the solution. Theresulting bottle was sonicated in a water bath at room temperature for40 minutes to disperse and dissolve the suspension, resulting in ahomogeneous solution.

Steroid Formulation No. 120:

120.A. Into a 30 ml glass beaker with a magnetic stir bar was added 55mg of 5-cholesten-3β,25-diol, 2.0 ml of absolute ethanol, 10 drops ofDMSO and 8.0 ml of a stock sterile aqueous solution comprising 0.0001%polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol %),Poloxamer 237 (0.05 wt/vol %), edetate disodium (0.05 wt/vol %), sodiumchloride (0.9 wt/vol %) and potassium chloride (0.05 wt/vol %) in doubledistilled water. The resulting solution was stirred at room temperaturefor 15 minutes where a small amount of insoluble beige particulatesremain present as a suspension in the solution. The solution wastransferred to a 10 ml sealable plastic (PET, LDPE) liquid dropperbottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous, slightly turbidsolution.

120.B. Into a 30 ml glass beaker with a magnetic stir bar was added 55mg of 5-cholesten-3β,25-diol, 2.0 ml of absolute ethanol, 10 drops ofDMSO and 8.0 ml of a stock sterile aqueous solution comprising 0.0001%polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol %),Poloxamer 237 (0.05 wt/vol %), polysorbate 80 (0.1 wt/vol %), castor oil(0.1 wt/vol %), edetate disodium (0.05 wt/vol %), sodium chloride (0.9wt/vol %) and potassium chloride (0.05 wt/vol %) in double distilledwater. The resulting solution was stirred at room temperature for 15minutes where a small amount of insoluble beige particulates remainpresent as a suspension in the solution. The solution was transferred toa 10 ml sealable plastic (PET, LDPE) liquid dropper bottle and capped toseal the solution. The resulting bottle was sonicated in a water bath atroom temperature for 40 minutes to disperse and dissolve the suspension,resulting in a homogeneous solution. Steroid Formulation No. 121:

121.A. Into a 30 ml glass beaker with a magnetic stir bar was added 100mg of sodium cholesteryl sulfate, 2.0 ml of absolute ethanol, 10 dropsof DMSO and 8.0 ml of a stock sterile aqueous solution comprising0.0001% polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol%), Poloxamer 237 (0.05 wt/vol %), edetate disodium (0.05 wt/vol %),sodium chloride (0.9 wt/vol %) and potassium chloride (0.05 wt/vol %) indouble distilled water. The resulting solution was stirred at roomtemperature for 15 minutes where a small amount of insoluble beigeparticulates remain present as a suspension in the solution. Thesolution was transferred to a 10 ml sealable plastic (PET, LDPE) liquiddropper bottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous, slightly turbidsolution.

121.B. Into a 30 ml glass beaker with a magnetic stir bar was added 100mg of sodium cholesteryl sulfate, 2.0 ml of absolute ethanol, 10 dropsof DMSO and 8.0 ml of a stock sterile aqueous solution comprising0.0001% polyhexamethylene biguanide (PHMB), phosphate buffer (0.2 wt/vol%), Poloxamer 237 (0.05 wt/vol %), polysorbate 80 (0.1 wt/vol %), castoroil (0.1 wt/vol %), edetate disodium (0.05 wt/vol %), sodium chloride(0.9 wt/vol %) and potassium chloride (0.05 wt/vol %) in doubledistilled water. The resulting solution was stirred at room temperaturefor 15 minutes where a small amount of insoluble beige particulatesremain present as a suspension in the solution. The solution wastransferred to a 10 ml sealable plastic (PET, LDPE) liquid dropperbottle and capped to seal the solution. The resulting bottle wassonicated in a water bath at room temperature for 40 minutes to disperseand dissolve the suspension, resulting in a homogeneous solution.

Alternative Topical Vehicle Solutions:

Double distilled H₂O was added to 1.1 g (EDTA)₂Na combined with 0.055 galkyldimethylbenzylammonium chloride until a final volume of 1.1 L (pH5.66) was achieved.

Excipients:

Sterile water (Ophthalmic grade isotonic solution, pH 6.3 to 6.5)buffered with potassium phosphate dibasic and potassium phosphatemonobasic; benzyl alcohol (preservative); glycerin (lubricant) 1.0% andCarboxymethylcellulose sodium (lubricant) 0.3%.

Preparation of Drug-loaded Nanoparticles:

A combination of a steroid formulation disclosed in Tables 1 to 8 isloaded into a lipid polymer hybrid nanoparticle through an adaptednano-precipitation method. The desired concentration of the steroidformulation is mixed with polycaprolactone (PCL) polymer dissolved inacetonitrile. Lecithin and1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethyleneglycol) 2000 (DSPE-PEG-COOH) are dissolved in a 4% ethanol aqueoussolution at 20% of the PCL polymer weight and is heated above 60 ° C.The steroids/PCL solution is added into the preheated lipid solutionunder gentle stirring followed by rigorous vortexing for 3 min. Themixture solution is stirred for 2 h to allow the nanoparticles to formand the acetonitrile to evaporate. The nanoparticle solution is washedthree times using an Amicon Ultra-4 centrifugal filter (Millipore) witha molecular weight cut-off of 10 kDa to remove the remaining organicsolvent and free molecules.

The resulting nanoparticles are then re-suspended in PBS buffer forsubsequent use. The size, size distribution and surface zeta potentialof the drug-loaded nanoparticles are characterized by dynamic lightscattering. The loading yield of the steroid formulation is quantifiedby high-performance liquid chromatography.

Treatment of Cataractous Lenses in Dogs:

The following adult dog breeds are used for assessing the treatmenteffect: black Labrador, Queensland Heeler and Miniature Pinscher. Alldogs are adult, non-diabetic and have normal ocular surfaces and ocularadnexa, with naturally occurring adult onset cataracts. There are nearequal distributions of male and female dogs. All exons of the LSS geneare screened in these dogs and there is no mutations. To assess theeffect of the steroid formulation treatment on cataracts in liveanimals, dogs are pre-medicated with intramuscular injections ofacepromaxine and butorphanol. After 20 min, induction of anesthesia isperformed by application of intravenous propofol.

Dogs are then immediately intubated and maintained on oxygen and 2%isoflurane at 2 ltr/min. The steroid formulation (100 μg)-loadednanoparticles are initially injected into the vitreous cavity in thetest eye using a 28-gauge needle, and then are given every 3 days forthe duration of the experiment. Treatment eyes or sham eyes arerandomized. The control eye is given an injection with emptynanoparticle carriers as a negative control. The treatment eyes aretreated with the steroid formulation in topical eye drops (see below foreye drop formulation). One 50-ml drop of steroid formulation isadministered three times daily to the test eye over 6 weeks.

Degree of cataract severity is examined by slit lamp and photographed atthe beginning and the end of the 6-week treatment period. Prior toexaminations, pupils are dilated with 1% tropicamide and 10%phenylephrine. Degree of cataract severity is assessed by a blindedexaminer and scored based on canine cataract stage. Improvements in lensclarity and transparency are quantified. Wilcoxon test is used toevaluate the treatment effect.

Topical Vehicle Solution:

Double distilled water is added to 1.1 g (EDTA)₂Na combined with 0.055 galkyldimethyl benzylammonium chloride until a final volume of 1.1 liters(pH 5.66) is achieved. 25 mM of the steroid formulation in the topicalvehicle solution. Double distilled H₂O is added to a mixture of 12.5 gsteroid formulation, 1.1 g (EDTA)₂Na, 0.055 g alkyldimethylbenzylammonium chloride and 200 ml EtOH to a final volume of 1.1 ltr.The vehicle solution was employed along with the additives andexcipients as noted in the specific formulations.

Drug Formulations:

Dry formulations were prepared and provided in different labeleddroppers. The formulations were prepared 3-5 days before administeringthe formulations to the dogs. The solutions were mixed only once andused for all experiments. When not used, the formulations were stored atroom temperature and protected from light.

Canine subjects:

Three dogs were administered with the selected formulations. Thefollowing adult dog breeds are used for assessing the treatment effect:Dog 1: Mixed breed; Dog 2: German Shepherd; Dog 3: Pekingese. Dogs arekept in indoor facilities, are very well fed and are treated completelyhumanely as adored house pets during the period of the experiments. Noneof the procedures employed in these experiments involve the exposure ofthe dogs to painful, stressful or noxious stimuli or processes.

Dog 1:

The treatment eyes, the left eyes (LE) and right eyes (RE), were treatedwith the two different formulations as follows: LE: Formulation 116.A;RE: Formulation 117.A.

Dog 2:

The treatment eyes, the left eyes (LE) and right eyes (RE), were treatedwith the two different formulations as follows: LE: Formulation 118.A;RE: Formulation 119.A.

Dog 3:

The treatment eyes, the left eyes (LE) and right eyes (RE), were treatedwith the two different formulations as follows: LE: Formulation 120.A;RE: Formulation 121.A.

Close-up photographs are taken of the eyes before any treatment.Photographs are also taken at the indicated time intervals on a dailyand/or weekly basis, after 1 week, 2 weeks and 3 weeks. All photographsare recorded to identify the specific dog, the eyes (left eye (LE) orright eye (RE) and the formulations used. 1 Drop of the formulation(about 50 μl) is administered three times daily at about 7 AM, 1 PM and4 PM, to the eyes, as indicated, over a period of 3 weeks.

RESULTS

Cataract grading system: Grade 0: absence of opacification (gridlinesclearly visible); Grade 1: A slight degree of opacification (minimalclouding of gridlines, with gridlines visible); Grade 2: Presence ofdiffuse opacification involving almost the entire lens (moderateclouding of gridlines, with main gridlines visible); Grade 3: Presenceof extensive, thick opacification involving the entire lens (totalclouding of gridlines, with gridlines not seen at all).

Based on the results noted in the RESULTS table, the administration ofthe formulations provided at least 5% to 20% percent improvement in theclarity of the lens, restoring protein solubility, improving solubilityof the a-crystallins, improving transparency and reversing proteinaggregation.

Dog 1:

Lens clarity of LE at day 7 showed at least 20% improvement overuntreated LE at day 1. Lens clarity of RE at day 7 showed at least about15% improvement over untreated RE at day 1.

Formulations 116.A and 117.A may provide at least 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 100%, 110%, 120%, 130%, 150%, 170%, 200%, 220%,240%, 260%, or 300% improvement in lens clarity over untreated lens. Forexample, dog lens with cataract grade 2 may improve to between grade 2and grade 1, less than grade 1, or grade 0 after 1 week, 2 weeks, 3weeks or 4 weeks with treatment with formulations 116.A and 117.A.

Dog 2:

Lens clarity of LE at day 7 showed at least 20% improvement overuntreated LE day 1. Lens clarity of RE at day 7 showed at least about15% improvement over untreated RE at day 1.

Formulations 118.A and 119.A may provide at least 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 100%, 110%, 120%, 130%, 150%, 170%, 200%, 220%,240%, 260%, or 300% improvement in lens clarity over untreated lens. Forexample, dog lens with cataract grade 2 may improve to between grade 2and grade 1, less than grade 1, or grade 0 after 1 week, 2 weeks, 3weeks, or 4 weeks with treatment with formulations 118.A and 119.A.

Dog 3:

Lens clarity of LE at day 7 showed at least 5% to 20% improvement overuntreated LE day 1. Lens clarity of RE at day 7 showed at least 5% to20% improvement over untreated RE at day 1.

Formulations 120.A and 121.A may provide at least 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 100%, 110%, 120%, 130%, 150%, 170%, 200%, 220%,240%, 260%, or 300% improvement in lens clarity over untreated lens. Forexample, dog lens with cataract grade 2 may improve to between grade 2and grade 1, less than grade 1, or grade 0 after 1 week, 2 weeks, 3weeks, or 4 weeks with treatment with formulations 120.A and 121.A.

As provided herein, the administration of the composition of the presentapplication as disclosed herein is effective in reversing cataracts in apatient and the treatment significantly reduces cataract severity andincreased lens clarity.

Pharmaceutical formulations can be prepared by procedures known in theart. For example, the compounds can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of diluents that aresuitable for systemic administration include water, saline and/orbuffered physiological solutions. Also, physiological preservatives(e.g., benzalkonium chloride), antibiotics, and compounds to adjust theosmolarity of the formulation of the solution may be included.

Other fillers and carriers which may also be employed, depending uponthe method of uptake, include the following: fillers and extenders suchas starch, sugars, mannitol, and silicic derivates; binding agents suchas carboxymethyl cellulose and other cellulose derivatives, alginates,gelatin and polyvinyl pyrrolidone; moisturizing agents such as glycerol;disintegrating agents such as agar, calcium carbonate, and sodiumbicarbonate; agents for retarding dissolution such as paraffin;resorption accelerators such as quaternary ammonium compounds; surfaceactive agents such as cetyl alcohol, glycerol monostearate; adsorptivecarriers such as kaolin and bentonite; and lubricants such as talc,calcium and magnesium stearate, and solid polyethyl glycols.

In one embodiment, the dose of steroids in a local concentration of thetherapeutic steroids that may range from 0.005 μM to 50 μM, or from 0.05nM to 1 μM, or from 1 nM to 100 nM; or as provided in the disclosedexamples herein.

In one embodiment, in order to obtain sustained contact of thecomposition with the eye and increased delivery of the steroidformulation to the eye, the concentration in the lachrymal fluid and inthe target tissue, may remain above the MIC₉₀ for the steroids. As usedherein, the “effective residence time” means a period of time followingapplication of the composition to the eye during which the concentrationof the steroids in the lachrymal fluid and/or in the target tissueremains above the MIC₉₀ for the steroids. In one variation, no more than3 drops, no more than 2 drops, or no more than 1 drop, each drop with ofabout 5 μl to about 50 μl, about 15 μl to about 30 μl, for example about25 μl, may contain the desired dose of the steroids for administrationto an eye. Administration of a larger volume to the eye may be possible,but risks loss of a significant portion of the applied composition bylachrymal drainage. In one variation, the composition is an in situgellable aqueous composition or formulation, such as an in situ gellableaqueous solution. Such a composition comprises a gelling agent in aconcentration effective to promote gelling upon contact with the eye orwith lachrymal fluid in the exterior of the eye. In some circumstances,it may be advantageous to formulate a composition of the presentapplication as a gel, to minimize loss of the composition immediatelyupon administration, as a result for example of lacrimation caused byreflex blinking.

In one variation, the formulation may further include at least one agentthat improves ocular tolerance, such as aloe vera gel, a buffering agentand a tonicity modifier. In another variation, the formulation mayinclude an antimicrobial agent and/or a preservative.

In certain embodiments, an appropriate amount of a calcium complexingagent such as ethylene diamine tetraacetic acid (EDTA) or a salt, suchas a disodium salt of the agent, may be included in the composition tocomplex ions, such as calcium ions and prevent gel formation duringstorage. EDTA or a salt thereof may be included in an amount of about0.01% to about 0.5%. Where a preservative is present, EDTA or a saltthereof may be included. In one aspect, disodium EDTA, in an amount ofabout 0.025% to about 0.1%, by weight, may be used to enhanceantimicrobial activity.

A composition of the present application may contain an antimicrobiallyeffective amount of a preservative, provided that the preservative doesnot substantially inhibit the effectiveness of the steroids orformulation or of any solubilizing agent in the composition. In onevariation, the formulation may contain a preservative selected from thegroup consisting of imidazolidinyl urea in an amount of about 0.03% toabout 0.5%; methylparaben in an amount of about 0.015% to about 0.25%;propylparaben in an amount of about 0.005% to about 0.01%;phenoxyethanol in an amount of about 0.25% to about 1%; disodium EDTA inan amount of about 0.05% to about 0.2%; thimerosal in an amount of0.001% to about 0.15%; chlorobutanol in an amount of about 0.1% to about0.5%; sorbic acid in an amount of about 0.05% to about 0.2%;benzalkonium chloride in an amount of about 0.001% to about 0.02%; anysuitable combination of any of the above. All amount figures above areprovided as a percent by weight of the total composition.

In another variation, the composition of the application may furthercomprise an ophthalmically compatible antioxidant. Such antioxidants mayinclude sodium bisulfite, sodium metabisulfite, sodium thiosulfate,acetyl cysteine, cysteine, thioglycerol, sodium sulfite, acetone sodiumbisulfite, dithioerythreitol, dithiothreitol, thiourea, propyl gallate,methionine and erythorbic acid.

In another variation, the composition may further comprise glycerin inan amount of about 0.1% to about 5%, more preferably about 1% to about2.5%, for example about 1.5% to about 2%, by weight. Glycerin can alsobe useful to increase viscosity of the composition and for adjustment ofosmolality.

In another variation, the composition or formulation is a topicalophthalmic composition formulated for application to the eye, whereinthe composition comprises a therapeutically effective amount of asteroid formulation as disclosed herein and a flowable crosslinkedcarboxy-containing polycarbophil mucoadhesive polymer, wherein thecomposition has a viscosity in the range of about 1,000 to about 3,400cps and a pH of about 7.4 to about 8.5. In another variation of thecomposition, the flowable mucoadhesive polymer is in an amount of about0.5% to about 1.5% by weight of the composition. In another variation,the steroid formulation is in an amount of about 0.005% to about 0.5% byweight of the composition.

The crosslinked or lightly crosslinked polymers of acrylic acid used inthe present application are known in the art. In one embodiment, thepolymers are prepared from at least about 90% or from about 95% to about99.9% by weight, based on the total weight of monomers present, of oneor more carboxyl-containing monoethylenically unsaturated monomers.Acrylic acid is a carboxyl-containing monoethylenically unsaturatedmonomer, but other unsaturated, polymerizable carboxyl-containingmonomers, such as methacrylic acid, ethacrylic acid, β-methylacrylicacid (crotonic acid), cis-α-methylcrotonic acid (angelic acid),trans-α-methylcrotonic acid (tiglic acid), α-butylcrotonic acid,α-phenylacrylic acid, α-benzylacrylic acid, β-cyclohexylacrylic acid,β-phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamicacid), umbellic acid (p-hydroxycoumaric acid), and the like can be usedin addition to or instead of acrylic acid. Such polymers are crosslinkedby using less than about 5%, such as from about 0.5% or from about 0.1%to about 5%, or from about 0.2% to about 1%, based on the total weightof monomers present, of a polyfunctional crosslinking agent. Suchcrosslinking agents are non-polyalkenyl polyether difunctionalcrosslinking monomers such as divinyl glycol;2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene; divinylbenzene;N,N-diallylacrylamide; N,N-diallylmethacrylamide and the like. Alsoincluded are polyalkenyl polyether crosslinking agents containing two ormore alkenyl ether groupings per molecule, or alkenyl ether groupingscontaining terminal H₂C═C<groups, prepared by etherification of apolyhydric alcohol containing at least four carbon atoms and at leastthree hydroxyl groups with an alkenyl halide such as allyl bromide, suchas polyallyl sucrose, polyallyl pentaerythritol; see for example U.S.Pat. No. 2,798,053. Diolefinic non-hydrophilic macromeric cros slinkingagents having molecular weights of from about 400 to about 8,000, suchas insoluble di- and polyacrylates and methacrylates of diols andpolyols, diisocyanate-hydroxyalxyl acrylate or methacrylate reactionproducts, and reaction products of isocyanate terminated prepolymersderived from polyester diols, polyether diols or polysiloxane diols withhydroxyalkylmethacrylates, can also be used as the crosslinking agents;see U.S. Pat. Nos. 4,192,827 and 4,136,250.

The lightly crosslinked polymers may be made from a carboxyl-containingmonomer or monomers as the sole monoethylenically unsaturated monomerpresent, together with a crosslinking agent or agents. The polymers canalso be polymers in which up to about 40%, or from about 0% to about 20%by weight, of the carboxyl-containing monoethylenically unsaturatedmonomer or monomers has been replaced by one or morenon-carboxyl-containing monoethylenically unsaturated monomerscontaining only physiologically and ophthalmologically innocuoussubstituents, including acrylic and methacrylic acid esters such asmethyl methacrylate, ethyl acrylate, butyl acrylate,2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate,3-hydroxypropylacrylate, vinyl acetate, N-vinylpyrrolidone; see U.S.Pat. No. 4,548,990 for a listing of such additional monoethylenicallyunsaturated monomers. In one embodiment, polymers are lightlycrosslinked acrylic acid polymers wherein the crosslinking monomer is2,3-dihydroxyhexa-1,5-diene or 2,3-dimethylhexa-1,5-diene.

In one embodiment, the lightly crosslinked polymers used in the presentspecification may be prepared by suspension or emulsion polymerizing themonomers, using conventional free radical polymerization catalysts, to adry particle size of not more than about 50 μm in equivalent sphericaldiameter; for example to provide dry polymer particles ranging in sizefrom about 1 to about 30 μm, or from about 3 to about 20 μm, inequivalent spherical diameter. These polymers may range in molecularweight of about 25,000 to about 4,000,000, or about 500,000 to about2,000,000.

In another variation, the formulation is an ophthalmic compositioncomprising a therapeutically effective amount of the steroid formulationand a flowable mucoadhesive polymer that is a crosslinkedcarboxy-containing polycarbophil, wherein the composition has aviscosity in the range of about 1,000 to about 3,400 cps and isformulated for administration to the eye of a mammal in drop form, thecomposition further comprises at least one additional non-steroidalanti-inflammatory agent, and the composition has a pH of about 7.4 toabout 8.5.

In another variation, the formulation is an ophthalmic compositioncomprising a flowable mucoadhesive polymer and a therapeuticallyeffective amount of the steroid formulation, wherein the composition hasa viscosity formulated for administration to the eye of a mammal in dropform. In another variation, the steroid formulation is retained in orcarried with the flowable mucoadhesive polymer. In another variation,the flowable mucoadhesive polymer is a sustained release deliverysystem. In another variation, the flowable mucoadhesive polymer is acarboxy-containing polymer, such as polycarbophil or DuraSite™. Inanother variation, the mucoadhesive polymer is in an amount of about0.5% to about 1.5% by weight of the composition. In another variation,the polymer is in an amount of about 0.8% to about 1.0% by weight of thecomposition. In another variation, the steroid formulation is in anamount of about 0.005% to about 0.5% by weight of the composition. Inanother variation, the steroid formulation is in an amount of about0.01% to about 0.2% by weight of the composition. In another variation,the steroid formulation is in an amount of about 0.045% to about 0.09%by weight of the composition. In another variation, the composition hasa pH of about 7.4 to about 8.5, or a pH of about 8.3. In anothervariation, the viscosity of the composition is in the range of about1,000 to about 2,000 centipoises (cps), or about 1,500 cps.

In another embodiment, there is provided a sustained release steroiddelivery system, including a flowable mucoadhesive polymer and atherapeutically effective amount of the steroid formulation in anophthalmic composition; wherein the flowable mucoadhesive polymer is inan amount of about 0.5% to about 1.5% by weight of the composition andthe steroid formulation is in an amount of about 0.005% to about 0.5% byweight of the composition; or about 0.045% to about 0.09% by weight ofthe composition. In another variation, the steroid formulation is in anamount of about 0.01% to about 0.2% by weight of the composition. Inanother variation, the steroid formulation is retained in or carriedwith the flowable mucoadhesive polymer. In another variation, theflowable mucoadhesive polymer is a carboxy-containing polymer, such aspolycarbophil or DuraSite™. In another variation, the steroidformulation is in an amount of about 0.01% to about 0.09% by weight ofthe composition, or about 0.8% to about 1.0% by weight of thecomposition. In another variation, the composition has a pH of about 7.4to about 8.5, or about 8.3. In another variation, the viscosity of thecomposition is in the range of about 1,000 to about 2,000 cps, or about1,500 cps.

In another embodiment, the disclosed formulations or compositions maycontain one or more surfactants and, if desired, one or more adjuvants,including additional medicaments, buffers, antioxidants, tonicityadjusters, preservatives, thickeners or viscosity modifiers. Thesurfactants employed in the formulation may include POE sorbitan fattyacid esters, hydrogentated castor oils, Polysorbate 60, polyoxythylenehydrogenated castor oil, Polysorbate 80, Polyoxyethylene HydrogenatedCastor Oil 60 and Poloxamer 407, and mixtures thereof.

Additives in the formulation may include sodium chloride, EDTA (disodiumedetate), and BAC (benzalkonium chloride) or sorbic acid, or both.

Compositions delivered by means of the sustained release medicamentdelivery system as disclosed herein may have residence times in the eyeranging from about 8 hours to about 24 hours. In one aspect, the steroidformulations contained in these compositions is released from thecomposition at rates that depend on such factors as the extent ofsteroid formulation loading and the pH of the system, as well as on anydrug delivery adjuvants, such as ion exchange resins compatible with theocular surface, where present. In another embodiment, the compositionprovides a sustained concentration of the steroid formulation of between10⁻⁸ and 10⁻⁴ M, in another embodiment between 10⁻⁷ and 10⁻⁵ M, in theaqueous or treated tissue of the eye for at least one hour, at least twohours, and in certain embodiments, at least three hours or more. Inanother embodiment, the composition provides sustained concentration ofthe steroid formulation of between 10⁻⁸ and 10⁻⁴ M, or between 10⁻⁷ and10⁻⁵ M, in the aqueous or treated tissue of the eye for at least twohours, at least three hours, or at least four hours or more.

In another embodiment, there is provided a process for the therapeutictreatment of the eye of a mammal including: (a) providing an ophthalmiccomposition comprising a steroid formulation in a therapeuticallyeffective amount of about 0.005% to about 0.5% by weight of thecomposition and a flowable mucoadhesive polymer in an amount of about0.5% to about 1.5% by weight of the composition; (b) administering thecomposition to the eye of a mammal in need thereof to treat a conditionselected from cataracts, inflammation or inflammatory conditions of theeye.

In another embodiment, there is provided a composition or a method forcombination therapy of the eye of a mammal comprising an ophthalmiccomposition having a therapeutically effective amount of a steroidformulation, a flowable mucoadhesive polymer such as DuraSite™ and oneor more additional non-steroidal anti-inflammatory agent such as, atherapeutically effective amount of ketorolac. In one variation of theabove, ketorolac is included in the composition of the invention in anamount of about 0.01% to about 1% by weight, about 0.4% to about 0.5% byweight of the composition. In one variation of the above, theformulation further comprises one or more agents selected from the groupconsisting of antibacterial agent, an antibacterial antibiotic agent,synthetic antibacterial agent, antifungal antibiotic agent, syntheticantifungal agent, antineoplastic agent, steroidal anti-inflammatoryagent, non-steroidal anti-inflammatory agent, anti-allergic agent,glaucoma-treating agent, antiviral agent and anti-mycotic agent.

According to another embodiments, aspects and variations of the presentapplication, the formulations or compositions may also include, inaddition to the steroid as an active agent, one or more other activeagents such as other NSAIDs. Suitable NSAIDs for combination therapyinclude aspirin, benoxaprofen, benzofenac, bucloxic acid, butibufen,carprofen, cicloprofen, cinmetacin, clidanac, clopirac, diclofenac,diflupredinate, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen,fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen,furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac,ketorolac, ketroprofen, lactorolac, lonazolac, metiazinic, miroprofen,nepafenac, naproxen, norketotifen, oxaprozin, oxepinac, phenacetin,pirprofen, pirazolac, protizinic acid, sulindac, suprofen, tiaprofenicacid, tolmetin, and zomepirac.

In another embodiment, the ophthalmic formulations may further compriseone or more additional therapeutically-active agents, includingantibacterial antibiotics, synthetic antibacterials, antifungalantibiotics, synthetic antifungals, antineoplastic agents, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,anti-allergic agents, glaucoma-treating agents, antiviral agents, andanti-mycotic agents that may include their esters, alcohols and acidsderived from the active agents.

Examples of the antibacterial antibiotics include aminoglycosides (e.g.,amikacin, apramycin, arbekacin, bambermycins, butirosin, dibekacin,dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin,micronomicin, neomycin, neomycin undecylenate, netilmicin, paromomycin,ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin andtrospectomycin), amphenicois (e.g., azidamfenicol, chloramphenicol,florfenicol, thiamphenicol), ansamycins (e.g., rifamide, rifampin,rifamycin sv, rifapentine and rifaximin), β-lactams (e.g., carbacephems(e.g., loracarbef), carbapenems (e.g., biapenem, imipenem, meropenem andpanipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole,cefatrizine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin,cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam,cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil,cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole,ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, ceifuzonam,cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine,cephalosporin, cephalothin, cephapirin sodium, cephradine andpivcefalexin), cephamycins (e.g., cefbuperazone, cefmetazole, cefininox,cefotetan, cefoxitin), monobactams (e.g., aztreonam, carumonam,tigemonam), oxacephems, flomoxef and moxalactam), penicillins (e.g.,amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin,aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinicacid, benzylpenicillin sodium, carbenicillin, carindacillin,clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin,methicillin sodium, mezlocillin, nafcillin sodium, oxacillin,penamecillin, penethamate hydriodide, penicillin g benethamine,penicillin g benzathine, penicillin g benzhydrylamine, penicillin gcalcium, penicillin g hydrabamine, penicillin g potassium, penicillin gprocaine, penicillin n, penicillin o, penicillin v, penicillin vbenzathine, penicillin v hydrabamine, penimepicycline, phenethicillinpotassium, piperacillin, pivampicillin, propicillin, quinacillin,sulbenicillin, sultamicillin, talampicillin, temocillin andticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin,lincomycin), macrolides (e.g., azithromycin, carbomycin, clarithromycin,dirithromycin, erythromycin, erythromycin acistrate, erythromycinestolate, erythromycin glucoheptonate, erythromycin lactobionate,erythromycin propionate, erythromycin stearate, josamycin, leucomycins,midecamycins, miokamycin, oleandomycin, primycin, rokitamycin,rosaramicin, roxithromycin, spiramycin and troleandomycin), polypeptides(e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin,enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin,polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton,tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin,virginiamycin and zinc bacitracin), tetracyclines (e.g., apicycline,chlortetracycline, clomocycline, demeclocycline, doxycycline,guamecycline, lymecycline, meclocycline, methacycline, minocycline,oxytetracycline, penimepicycline, pipacycline, rolitetracycline,sancycline and tetracycline), and others (e.g., cycloserine, mupirocinand tuberin).

Examples of the synthetic antibacterials include 2,4-diaminopyrimidines(e.g., brodimoprim, tetroxoprim, trimethoprim), nitrofurans (e.g.,furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline,nifurpirinol, nifurprazine, nifurtoinol and nitrofurantoin), quinolonesand analogs (e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin,enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin,miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin andtrovafloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine,benzylsulfamide, chloramine-b, chloramine-t, dichloramine-t,2-formylsulfisomidine, 4-β-d-glucosylsulfanilamide, mafenide,4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfarnerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidocchrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, 4-sulfanilylsulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine and sulfisoxazole) sulfones (e.g.,acedapsone, acediasulfone, acetosulfone sodium, dapsone,diathymosulfone, glucosulfone sodium, solasulfone, succisulfone,sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium andthiazolsulfone), and others (e.g., clofoctol, hexedine, methenamine,methenamine anhydromethylene-citrate, methenamine hippurate, methenaminemandelate, methenamine sulfosalicylate, nitroxoline, taurolidine andxibornol).

Examples of the steroidal anti-inflammatory agents include21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, filuprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide.

Examples of the antifungal antibiotics include polyenes (e.g.,amphotericin b, candicidin, dennostatin, filipin, fungichromin,hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin,pecilocin and perimycin), others (e.g., azaserine, griseofulvin,oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidinand viridin). Examples of the synthetic antifungals include, but are notlimited to: allylamines (e.g., butenafine, naftifine and terbinafine),imidazoles (e.g., bifonazole, butoconazole, chlordantoin,chlormiidazole, clotrimazole, econazole, enilconazole, fenticonazole,flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole,omoconazole, oxiconazole nitrate and sertaconazole, sulconazole andtioconazole), thiocarbamates (e.g., tolciclate, tolindate, tolnaftate),triazoles (e.g., fluconazole, itraconazole, saperconazole andterconazole) others (e.g., acrisorcin, amorolfine, biphenamine,bromosalicylchloranilide, buclosamide, calcium propionate,chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazoledihydrochloride, exalamide, flucytosine, halethazole, hexetidine,loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione,salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin,ujothion, undecylenic acid and zinc propionate).

In another variation, the composition may further include at least oneophthalmically acceptable salt in an amount required to bring osmolalityof the composition into an ophthalmically acceptable range. In someaspects, the salts can also be antioxidants. Salts suitable for use inadjusting osmolality include those having sodium, potassium or ammoniumcations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; preferred saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate. Other solutes suitable for adjustment ofosmolality include sugars, for example dextrose, manitol, xylitol, andsucrose.

The composition of the present application may further include at leastone ophthalmically acceptable pH adjusting agent and/or buffer,including an acid such as acetic, boric, citric, lactic, phosphoric andhydrochloric acids; a base such as sodium hydroxide, sodium phosphate,sodium borate, sodium citrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and a buffer such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such an acid, base and/orbuffer may be included in an amount required to maintain pH of thecomposition in an ophthalmically acceptable range.

The composition may further comprise a buffering agent and/or an agentfor adjusting osmolality in amounts whereby the solution issubstantially isotonic and has a physiologically acceptable pH. Inanother variation, the composition may further comprise at least oneophthalmically acceptable surfactant, such as a nonionic surfactant toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In another variation, the composition may further comprisean ophthalmically acceptable mucoadhesive polymer selected from thegroup consisting of hydroxypropylmethylcellulose,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, polyethyleneoxide, acrylic acid/butyl acrylate copolymer, sodium alginate anddextran. In another aspect of the composition, one or more antioxidantscan be included to enhance chemical stability where required. Suitableantioxidants include ascorbic acid, sodium metabisulfite, sodiumthiosulfate and thioglycerol.

In another embodiment, the disclosed composition may be administered asa solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, apolymer, a film, an emulsion, or a suspension. In another embodiment,the composition may be incorporated into or coated onto a contact lensor drug delivery device, from which one or more compounds from thecomposition is delivered by diffusion, away from the lens or device; orone or more compounds are released in a temporally-controlled manner. Inthe case that the contact lens is required for vision correction whenthe lens is in use, the contact lens comprising the composition mayremain on the ocular surface or the eye. In another embodiment thatemploys a drug delivery device using the composition of the presentapplication, the drug delivery device may be formed from biodegradablematerials, or as permanent lens known in the art.

While a number of exemplary embodiments, aspects and variations havebeen provided herein, those of skill in the art will recognize certainmodifications, permutations, additions and combinations and certainsub-combinations of the embodiments, aspects and variations. Allreferences cited herein are incorporated by reference in their entirety.It is intended that the following claims are interpreted to include allsuch modifications, permutations, additions and combinations and certainsub-combinations of the embodiments, aspects and variations are withintheir scope.

What is claimed: 1-25. (canceled)
 26. An aqueous, isotonic ophthalmiccomposition comprising: a) a steroid selected from the group consistingof 5-cholesten-3β-OSO₃H,25-ol (5-cholesten-3β-sulfate,25-ol),5-cholesten-3β,25-diol, lanosterol and 5-cholesten-3β-ol sulfate sodiumsalt, or a pharmaceutically acceptable salt thereof, or a combinationthereof; and b) a pharmaceutical excipient comprising2-hydroxypropyl-β-cyclodextrin (CD) and hydroxypropyl methylcellulose(HPMC); wherein the composition comprises water and ethanol; and whereinthe amount of the steroid or a mixture of steroid in the composition isin the range of 0.01% to 0.5% wt/wt.
 27. The aqueous, isotonicophthalmic composition of claim 26, wherein the pharmaceuticallyacceptable salt is a sodium salt.
 28. The aqueous, isotonic ophthalmiccomposition of claim 26, wherein the compound is5-cholesten-3β-OSO₃H,25-ol.
 29. The aqueous, isotonic ophthalmiccomposition of claim 26, wherein the compound is 5-cholesten-3β-olsulfate sodium salt.
 30. The aqueous, isotonic ophthalmic composition ofclaim 26, wherein the compound is 5-cholesten-3β,25-diol or apharmaceutically acceptable salt thereof.
 31. The aqueous, isotonicophthalmic composition of claim 26, wherein the compound is a mixtureconsisting of 5-cholesten-3β-OSO₃H,25-ol (5-cholesten-3β-sulfate,25-ol),5-cholesten-3β,25-diol, lanosterol and 5-cholesten-3β-ol sulfate sodiumsalt, or a pharmaceutically acceptable salt thereof.
 31. The aqueous,isotonic ophthalmic composition of claim 26, wherein the compound is5-cholesten-3β,25-diol.
 32. The aqueous, isotonic ophthalmic compositionof claim 26, wherein the compound is lanosterol.
 33. A method for thetreatment of cataracts, the method comprising an administration of anaqueous, isotonic ophthalmic composition comprising: a) a steroidselected from the group consisting of 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol), 5-cholesten-3β,25-diol, lanosterol and5-cholesten-3β-ol sulfate sodium salt, or a pharmaceutically acceptablesalt thereof, or a combination thereof; and b) a pharmaceuticalexcipient comprising 2-hydroxypropyl-β-cyclodextrin (CD) andhydroxypropyl methylcellulose (HPMC); wherein the composition compriseswater and ethanol; and wherein the amount of the steroid or a mixture ofsteroid in the composition is in the range of 0.01% to 0.5% wt/wt; to apatient in need thereof, wherein the administration of the compositionreverses protein aggregation in cataracts or significantly reduces theseverity of the cataract and increases the lens clarity, or inhibitsaggresome formation of both wild-type and mutated crystalline proteins.34. The method of claim 33, wherein the administration is by topicaladministration.
 35. The method of claim 33, wherein the administrationis by intracameral administration.
 36. The method of claim 33, whereinthe steroid is 5-cholesten-3β-OSO₃H,25-ol(5-cholesten-3β-sulfate,25-ol), or a pharmaceutically acceptable saltthereof.
 37. Them method of claim 35, wherein the steroid is lanosterol,or a pharmaceutically acceptable salt thereof.
 38. The method of claim31, wherein the steroid is 5-cholesten-3β-ol sulfate sodium salt, or apharmaceutically acceptable salt thereof.
 39. The method of claim 31,wherein the steroid is 5-cholesten-3β,25-diol, or a pharmaceuticallyacceptable salt thereof.